11.2018 | THE SCIENTIST 55CREDIT LINE
HUDA ZOGHBI
Professor, Baylor College of Medicine, Houston, Te x a s
Founding director of the Jan and Dan Duncan Neurological
Research Institute at Te x a s Children’s Hospital
Howard Hughes Medical Institute investigator
National Academy of Sciences member
Vilcek Prize in Biomedical Science, 2009
The Shaw Prize Laureate in Life Science and Medicine,
The Shaw Prize Foundation, Hong Kong, 2016
2017 Breakthrough Prize in Life Sciences
Canada Gairdner International Award, 2017Greatest Hits- Discovered the X-linked gene,MECP2, encoding a methyl-CpG-
binding protein, a mutation in which results in Rett syndrome,
a rare neurodevelopmental disorder that almost exclusively
affects girls. - Created a mouse model of Rett syndrome and uncovered
the cell type–specific requirements for Mecp2 in the brain. - Identified that low expression of Mecp2 results in Rett-like
features, while overexpression of the gene results in a
different neurodevelopmental disorder that includes autism-
like symptoms. - Along with the lab of Harry Orr, discovered the gene mutated
in spinocerebellar ataxia - Identified the Atoh1 gene, which encodes a transcription
factor essential for development of inner ear hair cells and the
Merkel cells of mammalian skin for the light-touch response,
to discriminate shapes and textures.
point. Still, Zoghbi hypothesized that Rett syndrome disrupts a
specific biological process and has a genetic basis, because the
symptoms are consistent from patient to patient. She wanted to
do additional Rett syndrome research, but she had no prior lab
experience. So she decided to do a postdoc and zeroed in on the
lab of Arthur Beaudet, also at Baylor, who studied genetic meta-
bolic disorders.
Zoghbi laid out her case for pursuing the genetic basis of
Rett, including her access to more than 100 patients. Beau-
det told her that, although he would take her on as a postdoc,
finding a genetic cause for the rare disorder was too tall an
order and that she should find a more tractable project. She
took the advice and wrote a proposal for the National Insti-
tutes of Health Mentored Clinical Scientist Research Career
Development Award, also called the K08, which provides five
years of support for a clinical researcher who aims to establish
their own laboratory. Zoghbi suggested studying spinocerebellar
ataxia (SCA) type 1, an autosomal dominant, usually adult-
onset neurodegenerative disease for which a causative genetic
mutation was not yet known.
“I wrote the proposal before I had any publications, when I
had no clue how to do anything in the lab. But I had determi-
nation, and a good mentor and scientific question,” she says,
noting that the award, which Zoghbi won in 1985, was a lucky
break for her career. “I had five years of funding, and I told
myself that I will give science these five years and won’t quit
before then.”
By this time, she and William had a toddler and a four-month-
old infant. She took graduate courses, learning molecular biology
and genetic linkage mapping.
After three years, Zoghbi finally made progress: she approxi-
mately mapped the SCA locus to a region of human chromosome 6.THE BIOLOGY OF RETT SYNDROME
Beaudet eventually advised Zoghbi to apply for funding to start
her own laboratory. In 1988, she became an assistant profes-
sor at Baylor. Deciding not to heed the advice of Beaudet and
other colleagues, Zoghbi returned to studying Rett syndrome,
convinced that she could map the causative gene, which she
suspected was on the X chromosome. Over the next 10 years,
she and her lab members began to collect tissue samples from
families with two affected sisters, systematically comparing
each of their X chromosome genes. This project helped Zoghbi’s
lab, in 1992, to identify a region of the X chromosome that har-